Emergency Emergency anticoagulant reversalanticoagulant reversal

B Vigué, DAR, CHU Bicêtre

1 to 2% of the population are prescribed VKA (Vitamin K Antagonist)

- Annual incidence of hemorrhage is 4 to 13% [Hylek, Circulation, 2003]

In France 17139 admissions per year in Emergency Department (ED) for bleeding under VKA (Sié 2002).In 2 month in a french universitary ED: 198 major bleedings, 34 for intracranial bleedings

INR>5 : 150 to 450 cas in french county EDs

Risk for intracranial haemorrhage: 1% per year

VKA decreases thrombotic risk

- Cardiac Valves :

Stroke : 4% / patient - yearAspirine : 2,2% / patient - year

VKA : 1% / patient - year

- Auricular Fibrillation

Stroke around 4% / patient - year

- Phlebitis and pulmonary embolism

Risk of VKA therapy VKA increases the risk for intracranial bleeding 7 to 10 foldIncidence : 0.3 to 1% per yearMortality: 60%

VKA + intracranial haemorrhage expansion = 50% No VKA + intracranial haemorrhage expansion = 10%

Risk factors for bleeding under VKA

INR in over therapeutic zone (>4-5) HTAStarting treatment (first 3 month)

As soon as possible!!

FFP : fresh frozen plasma Risk of TRALI

PCC (Prothrombin Complex Factor) : 4 factors superior to FFPNo delay to normalize60 ml of PCC = 2000 ml of FFP But factor VII 1/2 life = 5-6 hours

Vitamin K : Delayed correction = 6 to 8 hours to be effective Which dose?Delayed correction

No randomized trial

Thromb Haemost, 1997, United Kingdom41 patients

Retrospective studyPCC : 25-50 U IX / kg vs FFP (800ml)Vitamine K in all cases (1-5 mg IV)

In 15 min : complete reversal for 28/29 patient with PCC and for 0/12 patients for PFC

60 ml PCC=

2000 ml of FFP

PCC superior to FFP for emergency reversal of VKA

Needing of effective availability in all hospitals

Administration «as soon as diagnostic confirmed»

Guidelines

PCC(20-30 UI/kg)

+

Vitamin K (5-10 mg)

In France : management of INR in over therapeutic zone in cas of bleeding (n=198)

Intravenous vitamine K alone = 44%Oral vitamine K alone = 5%Intravenous vitamin K = 41%PCC in association = 29%PCC alone = 7%FFP = 25%

Under dosing of PCC (15 UI/kg instead of 20-30)

Discrepancy between guidelines and reality (fear of thrombotic events, availability of product)

Sié, 2002

•PCCs are the most accurate solution to reverse anticoagulation

Fact and hypothesis

• Intracranial bleeding under VKA : 50% mortality during the first month

Stroke, 2001

Thromb Haemost, 1997

• Delayed management could impair the prognosis

“You wouldn't say that if you had seen a valve thrombosis”

• To evaluate the rapidity of correction of INR after administration of PCC during the managment of neurosurgical bleeding

Aim of the study

Methods

• Rapid intravenous administration (1 min) of two 2 doses of PCC (10 U/kg)

•Begining of surgical procedure immediately after

•Preparation of the operative room, installation of patient for craniotomy before any laboratory results or administration of PCC

•Laboratory study: PT and INR before infusions, between infusions, immediately after and 6 hours later

• Administration of oral vitamin K, 5 mg

• Inclusion criteria : patients under VKA admitted for intracranial bleeding requiring a neurosurgical procedure

Methods

Emergency situationBe aware of pressure Come back to real riskCome back to the basics

Create an emergency situation, a golden hourAll are involved; emergency physicians, surgeons, anaesthesists, nurses

•Preparation of the operative room, installation of patient for craniotomy before any laboratory results or administration of PCC

•Rapid intravenous administration (1 min) of two 2 doses of PCC (10 U/kg)

Methods

Dose of PCC: INR between 2 and 3,5 : administration of 10 to 20 UI/kg of factor IX to limit the thrombotic riskIn INR in over therapeutic zone, 20 to 30 UI/kg of factro IX (25 UI/kg =1 ml /kg of factor IX)

Administration:Rate of infusion slower than 4 ml/min : 68/4 = 17 mins !!

Do not wait for laboratory control of reversal!

•Laboratory study: PT and INR before infusions, between infusions, immediately after and 6 hours later

Methods

Do not wait for laboratory control of reversal! A race against time A place for bedside monitoring?

Methods

• Administration of oral vitamin K, 5 mg

Oral vitamin K , efficiency to reverse anticoagulation in 6 to 12 hous (Br J of Haematology, 2001)

Oral vitamin K, superior to sub-cutaneous vitamin K to reverse anticoagulation

(Ann Intern Med, 2001)

Oral vitamin K, equivalent to intravenous vitamin K to reverse anticooagulation

(Ann Intern Med, 2003)

Results

• 18 patients included

• 12 subdural haematoma, 6 intracerbral haematoma

• No thrombotic complication

• Outcome : 13 patients with GOS 1 to 1, 4 patients died (23%)

Sexe AgeReason for VKA GCS Volume Dose/kg GOS

1 F 80 FA 14 60 20,0 1

2 M 73 FA 9 80 22,5 2

3 M 81 FA 9 60 20,0 1

4 F 71 PHV 6 60 21,4 5

5 F 71 VTE 6 60 21,4 1

6 M 62 atherom 10 80 20,0 1

7 M 82 atherom 6 70 22,5 1

8 F 54 FA 7 60 25,0 2

9 M 58 PHV 3 80 20,0 510 F 86 AVC 6 60 30,0 211 F 70 FA 8 60 21,4 512 M 56 FA 14 80 28 113 F 73 FA 10 60 20 114 M 58 PHV 5 80 20 215 F 70 FA 14 80 20 116 M 62 VTE 5 70 25 317 M 78 PHV 13 70 25 118 F 86 VTE 5 60 22 5

admission 1 min 2 min 6-12 h

PT (%) 20±9 62±14 78±15 66±17PT (sec) 40±22 14±2 12±2 13±2

TCK (sec) 53±15 41±10 40±11 37±5TT (sec) 20±5 20±4 21±5 18±4

V (%) 111±25 107±25 109±23 111±25

II (%) 33±23 70±20 94±21 87±22VII+X (%) 15±10 57±15 78±17 65±30

Results

INR 3,95±1,611,39±0,271,18±0,151,34±0,27

Results

0

20

40

60

80

100

120

TP

(%

)

Temps

Arrivée 1 min 2 min 6h-12h

10UI/Kg PPSB 10UI/Kg PPSB

* *

*

Results

0

20

40

60

80

100

120

TP

(%

)

Temps

10UI/Kg PPSB 10UI/Kg PPSB

Arrivée 1 min 2 min 6h-12h

avec vitamine K

sans vitamine K

Results

10UI/Kg PPSB 10UI/Kg PPSB

INR

Time

Admission 1 min 2 min 6h-12h

with vitamin K

without vitamin K

0

1,5

3

4,5

6

7,5

Results

Progressive reinitiating of anticoagulation,

No thrombotic event

Discussion

• 23% patients died (30 to 60 % in our litterature analysis)• The gain of time improves the management of the urgent neurosurgery. No laboratory control are needed to begin the surgical procedure

•Think for vitamin K !!

Discussion

•Why PCC is not currrently used ?…

Conclusion (1/3)

• Ultra rapid reversal of anticoagulation without thrombotic events

• VKA reversal improves time to surgical procedure

• Outcome? Mortality?

Conclusion (2/3)

•There is no way to delay surgery•Life-threatening events •All urgent surgery (as peritonitis…)

• there is no way to delay the reversal of VKA•Lost time +++ if life-threatening bleedings : intracranial and others•Lost time +++ if major bleedings in EDs

Conclusion (3/3)

• Need of teaching program : fight against non scientific historic fears.

•Need of multicentric trials in France and Europen. Evaluate the acccuracy and the safety of PCC. Show PCC as an antidote

•As malignancy hyperthermia in anaesthesia care, organize the management of bleeding under VKA with standardized written procedure.

As soon as diagnosis confirmed

As soon as possible